The proposed research aims to validate a developmental model of epileptogenesis, and delineate surrogate markers for the epileptogenic process and for associated neuronal dysfunction. A major goal of Epilepsy Research, considered an Epilepsy Benchmark, is to intervene in the epileptogenic process and abort the development of epilepsy and of related cognitive dysfunction. This goal requires: (1) validating models leading to epilepsy (spontaneous recurrent seizures) and (2) having reliable criteria or "markers" for progressive epileptogenesis. The applicants have focused on the epileptogenic process culminating in temporal lobe epilepsy (TLE), and specifically on the potential causative role of prolonged febrile seizures (FS). An immature rodent model of prolonged FS has been characterized and has led to the discovery of molecular changes that promote hyperexcitability in the limbic circuit. Recent findings, using nocturnal video-EEG monitoring, indicate that a subset of adult animals that had experienced experimental prolonged FS early in life develop classical limbic seizures, with behavioral and EEG correlates. Therefore, the proposed research will test the hypotheses that the prolonged FS model can be used to predict TLE and hippocampal cognitive deficits, and that MRI lesions will serve as surrogate markers for epileptogenesis and/or hippocampal cognitive deficits. The project aims to (1) Determine the nature, distribution and time-course of abnormal MRI signals, (2) determine the value of MRI in predicting epileptogenesis, (3) determine the value of MRI in predicting the development of hippocampal neuronal dysfunction at the single cell and system levels. Based on exciting preliminary data, it is strongly believed that the outcome of this work will provide important data for future interventional strategies targeting mechanisms of disease processes - a major goal for this RFA.